Multiplex families with epilepsy Success of clinical and molecular genetic characterization
Multiplex families with epilepsy Success of clinical and molecular genetic characterization
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DOI：
10.1212/wnl.0000000000002404
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发表时间：
2016-02-23
期刊：
影响因子：
9.9
通讯作者：
Berkovic, Samuel F.
中科院分区：
文献类型：
--
作者：
Afawi, Zaid;Oliver, Karen L.;Berkovic, Samuel F.
目的：分析癫痫多发家系的临床症状和遗传方式，以揭示其分子遗传学基础。方法：通过对有2个或2个以上癫痫患者亲属的家系进行调查，将其分为癫痫综合征。家族被分为综合征，其中至少2名家族成员有一个特定的诊断。系谱进行了分析，并进行了分子遗传学研究，作为appropriate.Results：共211个家庭被确定在以色列的11年期间。共169例被分为广泛的家族性癫痫综合征组：61例全身性，22例局灶性，24例热性惊厥综合征，33例特殊综合征，29例混合性。共有42个家庭仍未分类。在49/211个家庭（23%）中鉴定出致病性变体。大多数发现于已建立的癫痫基因中（例如，SCN 1A，KCNQ 2，CSTB），但在11个家庭中，该队列有助于最初的发现（例如，KCNT1、PCDH19、TBC1D24）。我们扩大了已建立的癫痫基因的表型谱报告一个家族LAMC 3纯合子变异，其中的主要表型是癫痫与肌阵挛-张力缺乏性癫痫发作，和一个致病性SCN 1A变异的家庭，其中在5个兄弟姐妹的表型是广泛一致的Dravet综合征，一种疾病，通常发生sporadicely.Conclusion：共80%的家庭被成功地分类，致病性变异的23%。家族性电临床和遗传模式的成功表征突出了研究多重家庭及其对揭示癫痫遗传基础的贡献的价值。
Objective:To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis.Methods:Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate.Results:A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically.Conclusion:A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.